The present invention relates to a method of producing a uniform distribution of radioisotope on a surface of a device. Furthermore, this invention is directed to coated products prepared using the disclosed method. More specifically, this invention is directed at permanently affixing a radioisotope of interest on the surface of a medical device.
In recent years the treatment of medical ailments using implantable devices treated with radioactivity has gained prominence throughout the medical community. This is because the antiproliferative effect of ionizing radiation has been recognized, and used, to reduce proliferative cell growth including, cancer cell growth. An advantage of using radioactive devices to apply the radiotherapy treatment is that the dose of radioactivity is localized and minimizes the total overall dose given to the patient. For example, it has been proposed that over 95% of the radiation dose is delivered with 5-6 mm of the implantation site (Fishell et al 1996, which is incorporated by reference). Typical applications of medical devices, treated so that they are radioactive, include the treatment of localized lesions using radioactive implants, stents and/or brachytherapy wires, or for example, the treatment of aberrant cell growth using radioactively treated catheters, or catheters capable of accepting radioactive inserts (U.S. Pat. Nos. 5,213,561; 5,484,384; 5,498,227; 5,575,749; WO 93/04735; Violaris et al 1997; Carter et al 1996; Fischell et al 1996; Hehrlein et al 1995, Wong and Leon 1995, which are all incorporated by reference). Other medical devices that are useful in treatment of cancers and the like include implantable radioactive sources, such as seeds etc (U.S. Pat. Nos. 4,815,449; 4,994,013; 5,342,283; 5,405,309, which are incorporated by reference).
Several important criteria for a radioactively treated medical device have been identified. It is generally desired within the art that medical devices treated with radioactivity exhibit a uniform, homogeneous distribution of radioisotope over the length and breadth of the device, and that the radioisotope be permanently affixed to the device and not leach out and contaminate the surrounding tissues when the device is implanted. The production of radioactive seeds comprising encapsulated radioactive sources (see U.S. Pat. Nos. 4,815,449; 4,994,013; 5,163,896; 5,575,749; WO 93/04735, which are incorporated by reference) meets the criteria for reducing the potential of isotope leaching during in vivo use, however, these devices result in high levels of micro-localized emissions of radiation at the location of the radioactive seed within the implant. Therefore, a significant drawback with such a device is the non-homogeneous delivery of ionizing radiation. In order to produce devices that exhibit negligible leaching and uniform isotope distribution, methods of ion implantation, wherein the isotope is imbedded within the structure of the stainless steel or metal device have been explored (U.S. Pat. No. 5,059,166; Fischell et al 1996; Violaris et al 1997). In addition, yields are low and difficult to control. Heavier elements are more difficult to ionize, requiring highly specialized, low reliability ion sources. As well, radioactive contamination of the ion source makes maintenance a safety hazard. Typical methods for the preparation of radioactively treated medical devices include bombarding non-radioactive metallic substrate with radioactive ions or transmutating the base material with protons or neutrons creating radioisotopes internally (e.g. U.S. Pat. Nos. 4,702,228; 5,405,309). Published work on pilot scale manufacturing methods of stents produced in this manner have been disclosed (Fehsenfeld et al 1991), however, these approaches for the preparation of radioactive devices are limited since they are one-at-a-time processes or involve extensive specialized equipment. Furthermore, only a range of substrates can be used that are compatible with the implantation technologies thereby limiting the selection of materials that can be used for the preparation of radioisotope-treated devices. For example palladium, enriched with palladium-102 can be used for transmutation by exposure to neutron flux, to produce palladium-103 (e.g. U.S. Pat. No. 4,702,228). Transmutation technologies utilizing protons or neutrons would also result in significant undesirable isotopes and associated radiation exposure to the patient in vivo. Furthermore, recovery costs for transmutation methods are high.
A dominant barrier for the application of the use of radioactively treated medical devices has been the lack of a commercially viable method for affixing the radioisotope to a medical device that meets the low leaching criteria required within the art.
Several reports comment, or mention in passing, the option of coating the surface of a medical device such as a stent with a radioisotope of interest (e.g. U.S. Pat. No. 5,213,561; Hehrlein 1995). However, no methods are provided for the preparation of such coated devices, nor are there any methods provided that could be used for the preparation of coated devices that would be suitable for medical application. Rather due to the stringent requirements of negligible, or no, isotope leaching from the radioactive device (e.g. Fischell et al 1996), coated medical devices have received poor reception within the art as it is expected that the coated radioisotope will leach while implanted in vivo. The generally accepted levels of isotope leaching for a coated medical device must be less than about 5% of the total isotope applied to the substrate. Preferably the amount of leachable radioisotope is less than 2%, and more preferably less than 1% of the total isotope applied. For example, Hehrlein et al (1995) differentiate radioactive stents produced using ion implantation, the use of which they characterize within their study for medical applications, from a coated stent which they considered to be non-applicable and lacking medical utility due to the expected degree of leaching, especially if the medical device needs to flex in any manner. The idea being that a coating would simply flake off the surface of the device and possibly enter the circulatory system.
An alternate solution for treating the exterior of a device has also been proposed that involves electro-plating the device, for example with gold-198 (U.S. Pat. Nos. 5,059,166; 5,167,617). This latter method applies to a limited range of isotopes and substrates that would be capable of being plated. It is, therefore well recognized within the art that present methods of coating devices with radioisotopes are deficient for the preparation of devices for use in radiotherapy.
There are many benefits associated with radiochemically coating devices. For example, the process is commercially scalable and allows for batch processing of high purity radioisotopes. Such a process combines uniform fixing and apyrogenic attributes for in vivo use, which is particularly important for high volume production. A large range of radioactivity and isotopes can be affixed uniformly, producing homogeneous coatings on a device and allowing customization of product. This process has a high utilization of isotopes, making it clean and efficient compared to other affixing methods. Furthermore, radiochemical coating of devices could utilize isotopes that are otherwise not available in devices prepared by ion implantation or transmutation methods. Similarly, a range of surfaces and non-metalic materials including synthetics, or other bio-compatible materials, could be coated with radioisotopes of interest for use. Thus there is a need to develop a simple method for preparing radioactively treated medical devices so that the radiochemical coating exhibits negligible or no leaching of the isotope in a test solution, or when implanted.
One study has examined the relative absorption of ions in dilute aqueous solutions on glass and plastic surfaces in order to determine the degree of contamination of these surfaces following their exposure to a range of isotopes (Eichholz et al 1965). The method employed adding the desired radioisotope to hard or distilled water and immersing the glass or plastic substrate within this solution for various lengths of time. Following a rinsing step using distilled water, the substrate was dried at 100xc2x0 C. and the remaining radioactivity of the substrate determined. They note that increasing the concentration of ions in the water-isotope mixture reduced the contamination of isotope on the substrate surface, and that decreasing the pH of this mixture also reduced contaminaton. No methods are disclosed that attempt to optimize the coating of the substrates with a radioisotope, nor is there any suggestion or disclosure of the use of such a method for the preparation and use of an isotopically coated device. Furthermore, there is no teaching of how permanent the coating of the substrate is, nor is there any information as to the degree of leaching of the isotope from the coated substrate. Rather, Eichholz et al were interested in reducing or eliminating radioactive contamination of glassware, whereas the method of this invention is directed to producing a uniform distribution of radioisotope on the surface of a medical device, as well as maximizing the yield and permanently affixing the radioisotope on the surface of the medical device.
It has been observed that following the methods of this invention, coated devices can be produced with high yield, if this is desired, with the coating applied in a uniform manner. Furthermore, leaching of the isotope from the surface of the coated substrate is markedly reduced over other processes for coating a surface of a substrate, for example, that involve a step of heating to dryness in order to affix the radioisotope onto the surface of the device. Lastly, the methods of this invention are readily applied to batch processing of a device to be coated, ensuring that coated substrates are produced with consistent coatings both within and between batches. Since there is negligible leachate of the coated radioisotope from the coated device, the coated devices as described herein are well suited for use within medical applications where a localized therapeutic treatment is desired.
It is an object of the invention to overcome disadvantages of the prior art.
The above object is met by the combinations of features of the main claims, the sub-claims disclose further advantageous embodiments of the invention.
The present invention relates to a method of producing a uniform distribution of radioisotope on a surface of a device. Furthermore, this invention is directed to coated products prepared using the disclosed method. More specifically, this invention is directed at permanently affixing a radioisotope of interest on the surface of a medical device.
The present invention pertains to a radioactively coated medical device characterized in that leachate from the coated substrate is of less than about 1%. Preferably the leachate is of less than about 0.5%.
This invention also includes a radioactively coated medical device as defined above that is coated with a radioisotope selected from the group consisting of Y-90, Pd-103, Pd-112, Co-55, Co-57, Co-60, Ag-110, Ag-111, Ag-112, Ag-113, Au-199, Cu-64, Re-186, Re-188, Ir-192, Ir-194, Mo-99, Ni-63, In-111, Tc-99, P-32, P-33, C-14, S-35, Cl-36, I-125, I-131, I-123, I-124, At-211, Gr-68, Ho-166, Gd-159, Pm-142, Gd-153, Yb-169, Am-241, and Yb-60.
This invention is also directed to the radioctively coated medical device as defined above wherein the medical device can comprise a variety of surface geometries, and is selected from the group consisting of: stent, expandable stent, catheter, delivery wire, source for brachytherapy, brachytherapy seed, source for an after-loader, seed, wire, protheses, valves, sutures and staples or other wound closure device. If a stent, this invention pertains to stents further characterized in having an axial uniformity of less than about 20%, and a radial uniformity of about 20%.
The present invention embraces a method of treatment of a patient in need thereof, comprising administering the coated radioactive device as defined above. The coated radioactive device as defined above may also be used for the treatment of cell proliferation.
The present invention also provides a first method for coating a substate with a radioisotope comprising:
a) pre-coating the substrate by immersing a cleaned substrate within a seeding solution containing an acid and a non-radioactive metal, at a temperature of between 90 and 95xc2x0 C. to produce a pre-coated substrate;
b) baking the precoated substrate at a temperature below the recrystallization temperature of the substrate;
c) immersing the precoated substrate within a matrix solution containing a xcex3, xcex2+, xcex1, xcex2xe2x88x92 or xcex5, emitting metallic radioisotope with a valence of two, at a temperature of between 90 and 95xc2x0 C. to produce a coated substrate;
d) baking the coated substrate at a temperature below the recrystallization temperature of the substrate;
The present invention relates to the above first method wherein the metallic radioisotope is selected from the group consisting of Y-90, Pd-103, Pd-112, Co-55, Co-57, Co-60, Ag-110, Ag-111, Ag-112, Ag-113, Pm-142, Am241, Gd-153, Gd-159, Yb-169, Ho-166, Au-199, Cu-64, Re-186, Re-188, Ir-192, Ir-194, Mo-99, Ni-63, In-111, and Tc-99m. Preferably the metallic radioisotope is Pd-103.
The present invention includes the above first method, wherein the matrix solution comprises a reducing agent and a stabilizing agent. For the coating of metallic Pd-103, preferably, the stabilizing agent is EDTA and the reducing agent is hydrazine sulfate, and the pH of the matrix solution is from about 7 to about 12.
This invention also pertains to the first method as defined above wherein the substrate is a medical device. Furthermore, the medical device can comprise a variety of surface geometries, and is selected from the group consisting of: stent, expandable stent, catheter, delivery wire, source for brachytherapy, brachytherapy seed, wire, seed, protheses, valves, and staples or other wound closure device. Preferably, the medical device is a stent, wire or seed. More preferably, the substrate is metallic. If metallic, preferably the substrate is stainless steel and nitinol.
The present invention is also directed to a medical device prepared using the first method as defined above, and to a method of treatment of a patient in need thereof, comprising administering the coated radioactive device.
The present invention also provides for a second method for coating a metallic medical device with a radioactive isotope comprising:
a) immersing the metallic medical device into an aqueous salt solution, at a pH of about 10 to about 12, and comprising a radioactive isotope, the metallic medical device acts as a first electrode;
b) inserting a second electrode with the aqueous salt solution;
c) applying a current to create a potential difference between the first and second electrodes;
d) removing the current, and rinsing the metallic medical device, allowing to air dry, and
e) optionally, baking at a temperature below the recrystallization temperature of the substrate.
Preferably, the metallic medical device is a silver medical device, and the radioactive isotope is selected from the group consisting of S-35, Cl-36, Mo-99, I-123, I-124, I-125, I-129, I-131, Pd-103, Ho-166, Y-90, P-32 and Ce-144.
The present invention also includes the second method defined above, wherein the step of applying, comprises applying a current of from about 15 xcexcA to 20 xcexcA, for about 2 hours.
The present invention also pertains to a medical device made by the second method as defined above. The medical device may comprise a variety of surface geometries, and is selected from the group consisting of: stent, expandable stent, source for after-loader, source for brachytherapy, brachytherapy seed, delivery wire, catheter, seed, wire, protheses, valves, sutures, and staples or other wound closure device. Preferably, the medical device is a stent.
Substrates coated using the methods of this invention, are produced with a uniform coating, improving over methods that simply employ evaporating the radioisotope to dryness. Furthermore, these coated devices can be produced with a high yield of radioisotope, and exhibit negligible, industrially or medically acceptable, rates of leaching of coated radioisotope. Furthermore, the methods of this invention are readily used for batch processing substrates thereby ensuring that coated substrates are produced with consistent coatings both with and between batches.
This summary of the invention does not necessarily describe all necessary features of the invention but that the invention may also reside in a sub-combination of the described features.